JP2003532726A - New anti-infective drug - Google Patents

Abstract

  (57) [Summary] Novel anti-infective agents and methods of using them are provided.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to novel anti-infective agents. Specifically, the present invention includes novel HCV inhibitors.

BACKGROUND OF THE INVENTION Hepatitis C virus (HCV) was first identified by molecular cloning in 1989 (Choo et al., 1989) and is now a non-A, non-B post-transfusion hepatitis (NAN).
It is widely recognized as the most common causative factor of BH) (Kuo et al., 1989)
. By virtue of its genomic structure and sequence homology, this virus can be identified as two other genera, flaviviruses (eg, yellow fever virus and dengue virus 1-
4) and pestiviruses (eg, bovine viral diarrhea virus, borderline virus, and classical swine fever virus) together with flavivirides (Flavivir).
idae) as a new genus (Choo et al., 1989; Miller and Purcel)
l, 1990). Like other members of Flaviviride, HCV is an enveloped virus that contains a positively directed, single-stranded RNA molecule. The HCV genome (see Figure 1) functions as an internal ribosome entry site (IRES) of approximately 3
It is approximately 9.6 kilobases (kb) containing a 40 base long and highly conserved non-cap 5'untranslated region (NTR) (Wang and Siddiqui, 1995). This element is followed by about 30 including both viral structural and non-structural proteins.
A region encoding a single long open reading frame (ORF) encoding a 00 amino acid polypeptide is followed. After invading the cytoplasm of cells, this RN
A is directly translated to approximately 3000 amino acids, including both viral structural and non-structural proteins (see Figure 2.1). This large polypeptide is then processed by the combination of host and virally encoded proteinases into individual structural and nonstructural proteins (reviewed in Rice, 1996). After the terminal stop codon of the long ORF, there are roughly three regions: a region of approximately 40 bases that is less conserved among different genotypes, a variable length poly (U) / polypyrimidine tract, and a "3'X-tail. There is a 3'NTR consisting of a highly conserved 98-base element, also called "(Kolykha
lov et al., 1996; Tanaka et al., 1995; Tanaka et al., 1996; Yamada et al.
., 1996). The 3'NTR is predicted to form a stable two-dimensional structure, which is essential for HCV growth in chimpanzees and is thought to function in the initiation and regulation of viral RNA replication.

Infection with HCV is the leading cause of human liver disease, which is widespread throughout the world with seroprevalence in the general community ranging from 0.3 to 2.2% (van der Poel et al., 1994),
It is as high as about 10 to 20% in Egypt (Hibbs et al., 1993). HCV is most commonly transmitted through the blood (Alter et al., 1993). An estimated 30% of these initial infections are symptomatic. However, more than 85% of all infected individuals become chronically infected (currently 3.9 million chronic infectious diseases in the US, 170 million chronic infectious diseases worldwide, estimated in 1994 in the US) 33,200 new cases). Chronic HCV infection is common in all cirrhosis, end-stage liver disease,
And accounts for 30% of liver cancer. 118,000 out of all chronic cases in the United States
Hepatocellular carcinoma (HCC) as a direct result of HCV infection in more than one case
) (Accounting for ≧ 25% of all liver cancers) (Hoofnagle, 1997; Seeff, 19
97). Currently, in the United States, HCV infection causes 8,000 ~
There were 12,000 deaths and the cost of treatment in the US in 1992 was an estimated 600 million. The CDC estimates that the number of deaths from HCV will increase to 38,000 / year by 2010.

Due to the high degree of variability in viral surface antigens, the presence of multiple viral genotypes, and the proven specificity of immunity, vaccine development is unlikely to succeed in the near future. At the beginning, the treatment consisted of only interferon, but now interferon α-2b (α-IFN, 3 million units of subcutaneous injection 3 times weekly) and ribavirin (1 to 1.2 g twice daily). Oral administration) combination treatment 24
Weeks or 48 weeks is the most effective approved treatment for the treatment of chronic HCV infection. Schering-Plough, 1998
Reported sales of $ 430 million on its own, specifically interferon alone for the treatment of HCV. Responses to sustained treatment and sustained response rates were better than interferon alone (80% initial response to the combination versus 46% initial response to IFN alone; and 30-50% sustained response to the combination versus sustained response to IFN alone 5 ~ 13%). However, there were still many adverse side effects associated with combination treatment (flu-like symptoms due to interferon, leukopenia, thrombocytopenia, depression, etc. and ribavirin-induced anemia) (reviewed in Lindsay, 1997). Has been). Furthermore, this treatment was less effective against infections caused by HCV genotype 1, which constitutes about 75% of all HCV infections in the development market (in contrast to other HCV genotypes). Target).
Similar to the treatment of HIV infection, combination therapy (ie IFN + antiviral drug or antiviral cocktail) is considered to be the most effective treatment.

In the United States, an estimated 3.9 million Americans are infected with HCV. Only 30% of acute infections are symptomatic, but> 85% of infected individuals develop chronic persistent infections. Currently, in the United States, HCV infection kills 8,000 to 10,000 people annually, and the cost of treatment is estimated at> 600 million / year (1992 CD for the United States.
C estimation). It is estimated that more than 170 million people worldwide are chronically infected. HCV infection causes 40-60% of all chronic liver diseases and 30% of all liver transplants. Vaccines are unlikely due to hypervariable surface antigens and proven immunospecificity.

Currently, there are no HCV antiviral drugs available and α-interferon (alone or in combination with ribavirin) is the only approved treatment. Treatment has many adverse side effects (flu-like symptoms, leukopenia, thrombocytopenia, depression, anemia, etc.); only about 50-80% of patients respond (lower serum HCV RNA levels, liver Enzyme normalization); however, 50-70% of treated individuals relapse within 6 months of discontinuing treatment.

The NS5B protein of HCV (591 amino acids, 65 kDa) (Behrens et a
l., 1996) encodes an RNA-dependent RNA polymerase (RdRp) activity,
It contains canonical motifs present in other RNA viral polymerases. NS5
B protein is in-type (one type 1b isolate versus another type 1b isolate, approximately 95-98%).
It is fairly well conserved both between aa) and between types (type 1a vs. type 1b, about 85% aa identity). HCV NS5B RdR for development of infectious progeny virions
The need for p-activity has been unequivocally demonstrated in chimpanzees (AA Kolykh
alov et al .. abstract, 1999), therefore, inhibition of NS5B RdRp activity is expected to be antiviral against HCV infection and inhibition of RNA replication is expected to treat infections.

Based on the above, there is a considerable need to identify synthetic or biological compounds for their ability to inhibit HCV.

SUMMARY OF THE INVENTION The present invention includes compounds shown below, pharmaceutical compositions containing such compounds and methods of using the compounds of the present invention.

[0010] (Detailed Description of the Invention)   Compounds useful in the methods of the present invention have the formula (I):

[Chemical 2] [Wherein A represents OR ₁ , NR ₁ R ₂ , or R ₁ , wherein R ₁ and R ₂ are hydrogen,
Selected from the group consisting of C _1-6 alkyl, optionally substituted aryl, alkylaryl, arylalkyl; B represents hydrogen, C (O) R ₁ , wherein R ₁ is hydrogen, C _1-6 alkyl, aryl, alkylaryl, arylalkyl selected from the group; C represents hydrogen, C _1-6 alkyl, or optionally substituted aryl; D is OR ₁ , NR ₁ R ₂ or R ₁ , wherein R ₁ and R ₂ are hydrogen,
Selected from the group consisting of C _1-6 alkyl, aryl, alkylaryl, arylalkyl; E represents hydrogen, C _1-6 alkyl, optionally substituted aryl, alkylaryl, arylalkyl; X is C _1-6 alkyl, optionally substituted aryl, alkylaryl,
Represents arylalkyl; n is 1 or 2 or 3].

Preferably A is selected from the group consisting of OH, OR ₁ ; preferably B is selected from the group consisting of C (O) R ₁ ; preferably C is substituted Optionally selected from the group consisting of aryl; preferably D is selected from the group consisting of OH, OR ₁ ; preferably E is hydrogen; preferably X is C _1-6 Selected from the group consisting of alkyl, alkylaryl; preferably n is 1 or 2.

As used herein, “alkyl” represents an optionally substituted hydrocarbon group linked together by a carbon-carbon single bond. The alkyl hydrocarbon group may be straight-chain, branched or cyclic, and saturated or unsaturated. Preferably the group is straight chain. Preferably the group is unsubstituted. Preferably the group is saturated. The preferred alkyl group is C _1-4 alkyl, most preferably methyl.

As used herein, “aryl” is optionally substituted having at least one ring having a conjugated π electron system, containing up to two conjugated bonds or fused ring systems. Represents a good aromatic group. “Aryl” means a carbocyclic aryl group,
Heterocyclic aryl groups and biaryl groups are mentioned, all of which may be substituted. A preferred aryl group is phenyl which is unsubstituted, monosubstituted, disubstituted or trisubstituted. Preferred heteroaryl groups are selected from the group consisting of unsubstituted, monosubstituted, disubstituted or trisubstituted thienyl, quinolinyl, indolyl and pyridinyl. Preferred aryl and heteroaryl substituents are from the group consisting of C _1-4 alkyl, NC _1-4 alkyl, halo, OC _1-4 alkyl, CH═CH, CF ₃ , pyridine, phenyl, NO ₂ , OH and MeO. To be selected.

More preferably, the alkyl substituent is methyl or ethyl. More preferably, the halo substituent is chloro or bromo.

A preferred compound useful in the present invention is 2-isobutyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid. 4-Methyl ester; 5- (3-Fluoro-phenyl) -2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (3-fluoro-
Phenyl) -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-isobutyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl ] -Pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
-(3-Methoxy-phenyl) -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 5- (2-chloro-5-trifluoromethyl-phenyl) -2-isobutyl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
4-dicarboxylic acid 4-methyl ester; 5- (2-chloro-5-trifluoromethyl-phenyl) -1- [1- (3,4-
Dichloro-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-benzyl-5- (2-chloro-5-trifluoromethyl-phenyl) -1-
[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4
-Dicarboxylic acid 4-methyl ester; 2-benzyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5-
Thiophene-2-yl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-benzyl-5- (3-fluoro-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -Pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
3-Fluoro-phenyl) -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-benzyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl ] -Pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 5- (3-bromo-4,5-dimethoxy-phenyl) -2-methyl-1- [1- (
4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-isobutyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl ) -Methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (3-fluoro-
Phenyl) -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
-(3-Methoxy-phenyl) -pyrrolidine-2,4-dicarboxylic acid;

5- (2-chloro-5-trifluoromethyl-phenyl) -1- [1- (3,4-
Dichloro-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid; 5- (2-chloro-5-trifluoromethyl-phenyl) -2-isobutyl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
4-dicarboxylic acid; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
-(2,3,5-trichloro-phenyl) -pyrrolidine-2,4-dicarboxylic acid; 5- (3-bromo-4,5-dimethoxy-phenyl) -2-methyl-1- [1- (
4-Trifluoromethyl-phenyl) -methanoyl] -pyrrolidin-2,4 dicarboxylic acid; 2-benzyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl]- Pyrrolidine-2,4-dicarboxylic acid; 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
3-Fluoro-phenyl) -pyrrolidine-2,4-dicarboxylic acid; 2-benzyl-5- (3-fluoro-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine- 2,4-Dicarboxylic acid; 2-benzyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 2- Benzyl-5- (2-chloro-5-trifluoromethyl-phenyl) -1-
[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4
-Dicarboxylic acid; 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
It is selected from the group consisting of 2,3,5-trichloro-phenyl) -pyrrolidine-2,4-dicarboxylic acid.

Also included in the present invention are pharmaceutically acceptable salt complexes. Ethylenediamine, sodium, potassium, calcium, ethanolamine, hydrochloride, hydrobromide and trifluoroacetate are preferred. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are considered to be within the scope of this invention.

Also included in the invention is a method according to Scheme 1 for the synthesis of the compound using a suitable solid phase such as Wang, Merrifield, BAL or other suitable resin.

[0019]

[Chemical 3]

The synthesis of the remaining compounds of formula (I) is carried out by methods analogous to those described above and in the experimental section, with appropriate manipulation and protection of chemical functional groups.

Example 1 Preparation of 2-isobutyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester a) Wang resin bound 4-methyl-2-[(thiophen-2-ylmethylene)-
Amino] -pentanoic acid Wang-bound Fmoc-L-leucine (5.0 g, loading 0.6 mmol / g) was suspended in a 20% piperidine / dimethylformamide solution (10 mL) and shaken for 20 minutes. The solution was decanted from the resin and again the resin was washed with a second fresh solution (1
0 mL) for 30 minutes. The resin was filtered and washed successively with dimethylformamide 3 times, dichloromethane 4 times, methanol 4 times and dichloromethane 3 times. A portion of the resin (0.5 g, 0.3 mmol) was suspended in toluene (7 mL) and treated with thiophene-2-carboxaldehyde (10 eq, 0.3 mL). The mixture was heated to 80 ° C. in an orbital sand bath and shaken for 16 hours. The mixture was cooled and filtered. The resin was washed 5 times with toluene.

B) Wang resin bound 2-isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester The compound of Example 1 (a) (0.5 g, 0.3 mmol) was added. Suspended in toluene (7 mL) and acetic acid (0.5 mL). The mixture was added to methyl acrylate (10 eq,
0.14 mL). The mixture was heated to 80 ° C. in an orbital sand bath and shaken for 12 hours. The resin was filtered and washed successively with toluene 4 times, dichloromethane 3 times, methanol 3 times and dichloromethane 3 times.

C) Wang resin bound 2-isobutyl-5-thiophen-2-yl-1- [1
-(4-Trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester The compound of Example 1 (b) (0.5 g, 0.3 mmol) was suspended in pyridine (8 mL). Turbid, 4-trifluoromethylbenzoyl chloride (10 eq, 0.5 mL)
Processed in. The mixture was shaken at room temperature for 14 hours. The resin was filtered and washed successively with dichloromethane three times, methanol four times and dichloromethane three times.

D) 2-Isobutyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Example 1 The compound of (c) was treated with neat trifluoroacetic acid for 10 hours. The solution was removed from the resin and the resin washed 3 times with dichloromethane. The TFA solution and wash were combined and evaporated. The residue was chromatographed using Gilson reverse phase HPLC to give the desired compound as a tan solid (21.
2 mg). MS [M + H] ⁺ 484.4.

Example 2 5- (3-Fluoro-phenyl) -2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Preparation of The title compound was prepared as a solid according to the method of Example 1 (a) -1 (d) except that 3-fluorobenzaldehyde was used instead of thiophene-2-carboxaldehyde. MS [M + H] ⁺ 496.4.

Example 3 1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (3-fluoro-
Preparation of phenyl) -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Using 3-fluorobenzaldehyde in place of thiophene-2-carboxaldehyde and 3,4 in place of 4-trifluoromethylbenzoyl chloride. According to the method of Example 1 (a) -1 (d) except that -dichlorobenzoyl chloride was used, the title compound was prepared as a solid. MS [M + H] ⁺ 496.4.

Example 4 2-Isobutyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Preparation of The title compound was prepared as a solid according to the method of Example 1 (a) -1 (d) except that m-anisaldehyde was used instead of thiophene-2-carboxaldehyde. MS [M + H] ⁺ 508.4.

Example 5 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
Preparation of-(3-methoxy-phenyl) -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester m-anisaldehyde was used in place of thiophene-2-carboxaldehyde and 3 in place of 4-trifluoromethylbenzoyl chloride. The title compound was prepared as a solid according to the method of Example 1 (a) -1 (d) except that 4,4-dichlorobenzoyl chloride was used. MS [M + H] ⁺ 508.2.

Example 6 5- (2-chloro-5-trifluoromethyl-phenyl) -2-isobutyl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
Preparation of 4-dicarboxylic acid 4-methyl ester According to the method of Example 1 (a) -1 (d) except that 2-chloro-5-trifluoromethylbenzaldehyde was used instead of thiophene-2-carboxaldehyde. The compound was prepared as a solid. MS [M + H] ⁺ 580.4.

Example 7 5- (2-chloro-5-trifluoromethyl-phenyl) -1- [1- (3,4-
Preparation of dichloro-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Using 2-chloro-5-trifluoromethylbenzaldehyde in place of thiophene-2-carboxaldehyde, 4- Example 1 (a) except that 3,4-dichlorobenzoyl chloride was used instead of trifluoromethylbenzoyl chloride.
The title compound was prepared as a solid according to the method of -1 (d). MS [M + H] ⁺ 580.4.

Example 8 2-Benzyl-5- (2-chloro-5-trifluoromethyl-phenyl) -1-
[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4
-Preparation of dicarboxylic acid 4-methyl ester Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 1 except starting with phenylalanine and substituting 2-chloro-5-trifluoromethylbenzaldehyde for thiophene-2-carboxaldehyde.
The title compound was prepared as a solid according to the method of (a) -1 (d). MS [M
+ H] ⁺ 614.4.

Example 9 Preparation of 2-benzyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
According to the method of Example 1 (a) -1 (d) except starting with phenylalanine,
The title compound was prepared as a solid. MS [M + H] ⁺ 518.4.

Example 10 2-Benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5-
Preparation of thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 1 (a) -1 (d) except starting with phenylalanine and substituting 3,4-dichlorobenzoyl chloride for 4-trifluoromethylbenzoyl chloride.
The title compound was prepared as a solid according to the method of 1.). MS [M + H] ⁺ 518.
4.

Example 11 2-Benzyl-5- (3-fluoro-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Preparation of Wang-bound Fmoc-L-leucine instead of Wang-bound Fmoc-L-
The title compound was prepared as a solid according to the method of Example 1 (a) -1 (d) except starting with phenylalanine and substituting 3-fluorobenzaldehyde for thiophene-2-carboxaldehyde. MS [M + H] ⁺ 530.4.

Example 12 2-Benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
Preparation of 3-fluoro-phenyl) -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 1 (except starting with phenylalanine and using 3-fluorobenzaldehyde instead of thiophene-2-carboxaldehyde and 3,4-dichlorobenzoyl chloride instead of 4-trifluoromethylbenzoyl chloride.
The title compound was prepared as a solid according to the method a) -1 (d). MS [M +
H] ⁺ 530.2.

Example 13 2-Benzyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Preparation of Wang-bound Fmoc-L-leucine instead of Wang-bound Fmoc-L-
The title compound was prepared as a solid according to the method of Example 1 (a) -1 (d) except starting with phenylalanine and substituting m-anisaldehyde for thiophene-2-carboxaldehyde. MS [M + H] ⁺ 542.4.

Example 14 5- (3-Bromo-4,5-dimethoxy-phenyl) -2-methyl-1- [1- (
Preparation of 4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
The title compound was prepared as a solid according to the method of Example 1 (a) -1 (d) except starting with alanine and substituting 3-bromoveratraldehyde for thiophene-2-carboxaldehyde. MS [M + H] ⁺ 574.4.

Example 15 Preparation of 2-isobutyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Methyl acrylate The title compound was prepared as a solid according to the method of Example 1 (a) -1 (d) except that tert-butyl acrylate (0.5 mL) was used instead. MS [M + H] ⁺ 470.0.

Example 16 1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (3-fluoro-
Preparation of (phenyl) -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid According to the method of Example 3 except that tert-butyl acrylate (0.5 mL) was used in place of methyl acrylate, the title compound was obtained as a solid. Manufactured. MS [M +
H] ⁺ 481.8.

Example 17 1- [1- (3,4-Dichloro-phenyl) -methanoyl] -2-isobutyl-5
Preparation of-(3-methoxy-phenyl) -pyrrolidine-2,4-dicarboxylic acid The title compound was prepared according to the method of Example 5 except that tert-butyl acrylate (0.5 mL) was used instead of methyl acrylate. Prepared as a solid. MS [M +
H] ⁺ 494.0.

Example 18 5- (2-chloro-5-trifluoromethyl-phenyl) -1- [1- (3,4-
Preparation of dichloro-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid According to the method of Example 7 except tert-butyl acrylate (0.5 mL) was used instead of methyl acrylate. The title compound was prepared as a solid. MS [M +
H] ⁺ 566.0.

Example 19 5- (2-chloro-5-trifluoromethyl-phenyl) -2-isobutyl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
Preparation of 4-dicarboxylic acid The title compound was prepared as a solid according to the method of Example 6 except tert-butyl acrylate (0.5 mL) was used in place of methyl acrylate. MS [M +
H] ⁺ 566.0.

Example 20 1- [1- (3,4-Dichloro-phenyl) -methanoyl] -2-isobutyl-5
Preparation of-(2,3,5-trichloro-phenyl) -pyrrolidine-2,4-dicarboxylic acid tert-butyl acrylate (0.5 mL) was used in place of methyl acrylate,
The title compound was prepared as a solid according to the method of Example 1 (a) -1 (d), except that 2,3,5-trichlorobenzaldehyde was used instead of thiophene-2-carboxaldehyde. MS [M + H] ⁺ 568.0.

Example 21 5- (3-Bromo-4,5-dimethoxy-phenyl) -2-methyl-1- [1- (
Preparation of 4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid According to the method of Example 14 except tert-butyl acrylate (0.5 mL) was used in place of methyl acrylate. The title compound was prepared as a solid. MS [M
+ H] ⁺ 562.0.

Example 22 Preparation of 2-benzyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Methyl acrylate The title compound was prepared as a solid according to the method of Example 9 except tert-butyl acrylate (0.5 mL) was used instead. MS [M +
H] ⁺ 504.0.

Example 23 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
Preparation of 3-Fluoro-phenyl) -pyrrolidine-2,4-dicarboxylic acid Following the method of Example 12 except substituting tert-butyl acrylate (0.5 mL) for methyl acrylate, the title compound was made as a solid. Manufactured. MS [M
+ H] ⁺ 516.0.

Example 24 Preparation of 2-benzyl-5- (3-fluoro-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Acrylic acid Following the method of Example 11 except substituting tert-butyl acrylate (0.5 mL) for methyl, the title compound was prepared as a solid. MS [M
+ H] ⁺ 516.0.

Example 25 Preparation of 2-benzyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Acrylic acid The title compound was prepared as a solid according to the method of Example 13 except tert-butyl acrylate (0.5 mL) was used in place of methyl. MS [M
+ H] ⁺ 528.0.

Example 26 2-Benzyl-5- (2-chloro-5-trifluoromethyl-phenyl) -1-
[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4
-Preparation of dicarboxylic acid The title compound was prepared as a solid according to the method of Example 8 except tert-butyl acrylate (0.5 mL) was used instead of methyl acrylate. MS [M +
H] ⁺ 600.0.

Example 27 2-Benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
Preparation of 2,3,5-trichloro-phenyl) -pyrrolidine-2,4-dicarboxylic acid tert-butyl acrylate (0.5 mL) was used in place of methyl acrylate,
The title compound was prepared as a solid according to the method of Example 9 except 2,3,5-trichlorobenzaldehyde was used instead of thiophene-2-carboxaldehyde. MS [M + H] ⁺ 601.8.

Also included in the invention is a method of synthesizing the compound according to Scheme 2 using a suitable solid phase such as Wang, Merrifield, BAL or other suitable resin.

[0052]

[Chemical 4]

The synthesis of the remaining compounds of formula (I) is carried out by methods analogous to those described above and described in the experimental section below, with appropriate manipulation and protection of chemical functional groups.

Example 28 1- [1- (3,4-Dichloro-phenyl) -methanoyl] -2-isobutyl-5
-Preparation of thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid a) Wang resin bound 4-methyl-2-[(thiophen-2-ylmethylene)-
Amino] -pentanoic acid Wang-bound Fmoc-L-leucine (5.0 g, 0.86 mmol / g load)
Was suspended in a 20% piperidine / dimethylformamide solution (10 mL) and shaken for 20 minutes. Decant the solution from the resin and again place the resin in a second fresh solution (10
(mL) for 30 minutes. The resin was filtered and washed successively with dimethylformamide 3 times, tetrahydrofuran 4 times, dichloromethane 4 times and methanol 4 times. A part of the resin (0.1 g, 0.088 mmol) was added to trimethyl orthoformate (2 mL).
), Thiophene-2-carboxaldehyde (10 eq, 0.08 mL)
). The mixture was shaken on a wrist shaker at room temperature for 16 hours. The mixture was filtered and washed successively with tetrahydrofuran 4 times and dichloromethane 8 times.

B) Wang resin bound 2-isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 4-tert-butyl ester The compound of Example 28 (a) (0.1 g, 0.086 mmol). ) Was suspended in acetonitrile (2 mL). The mixture was added to tert-butyl acrylate (3 eq, 0.03
8 mL), silver nitrate (3.5 eq, 51 mg), and triethylamine (3.5 eq, 0.042 ml). The mixture was shaken on a wrist shaker at room temperature for 16 hours. The mixture was filtered and washed successively with tetrahydrofuran 4 times and dichloromethane 8 times.

C) Wang resin bound 1- [1- (3,4-dichloro-phenyl) -methanoyl]
2-Isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 4-tert-butyl ester The compound of Example 28 (b) (0.1 g, 0.086 mmol) in acetonitrile (2 mL). Suspended, 3,4-dichlorobenzoyl chloride (5 eq, 0.09 g
), And triethylamine (5 eq, 0.06 mL). The mixture was shaken on a wrist shaker at room temperature for 16 hours. The mixture was filtered and washed successively with tetrahydrofuran 4 times and dichloromethane 8 times.

D) 1- [1- (3,4-Dichloro-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid Example 28 (c) The compound was treated with neat trifluoroacetic acid for 5 hours. The solution was removed from the resin and the resin washed 3 times with dichloromethane. The TFA solution and wash were combined and evaporated. The resin was chromatographed using Gilson reverse phase HPLC to give the desired compound as a solid (21.2 mg). M
S [M + H] ⁺ 471.4.

Example 29 2- (2-carbamoyl-ethyl) -5-thiophen-2-yl-1- [1- (4
Preparation of -trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (a) except starting with glutamine (Trt) and substituting 4-trifluoromethylbenzoyl chloride for 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of -28 (d). MS [M + H
] ⁺ 485.4.

Example 30 1- [1- (3,4-Dichloro-phenyl) -methanoyl] -2- (3H-imidazol-4-ylmethyl) -5-thiophen-2-yl-pyrrolidin-2,4- Preparation of dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
The title compound was prepared as a solid according to the methods of Examples 28 (a) -28 (d) except starting with histidine (Trt). MS [M + H] ⁺ 495.4.

Example 31 2- (3H-imidazol-4-ylmethyl) -5-thiophen-2-yl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
Preparation of 4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (a) except starting with histidine (Trt) and substituting 4-trifluoromethylbenzoyl chloride for 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of -28 (d). MS [M + H
] ⁺ 494.4.

Example 32 Preparation of 2-isobutyl-1- (1-phenyl-methanoyl) -5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid Benzoyl chloride instead of 3,4-dichlorobenzoyl chloride The title compound was prepared as a solid according to the method of Example 28 (a) -28 (d) except that was used. MS [M + H] ⁺ 402.4.

Example 33 Preparation of 2-isobutyl-1- (1-phenyl-methanoyl) -5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang bond Wang bond instead of Fmoc-L-leucine. Fmoc-L-
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except starting with serine (tBu) and substituting benzoyl chloride for 3,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 376.4.

Example 34 Preparation of 2-isobutyl-5-thiophen-2-yl-1- (1-o-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Instead of 3,4-dichlorobenzoyl chloride The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that o-toluoyl chloride was used. MS [M + H] ⁺ 416.5.

Example 35 Preparation of 1- [1- (4-chloro-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 3,4-dichlorobenzoyl The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 4-chlorobenzoyl chloride was used instead of chloride. MS [M + H] ⁺ 416.5.

Example 36 Preparation of 5-benzofuran-2-yl-2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Thiophene-2- Example 28 (a) -28 (except that benzofuran-2-carboxaldehyde was used in place of carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of d). MS [M + H] ⁺ 50
4.4.

Example 37 Preparation of 5-benzofuran-2-yl-2-carbamoylmethyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Wang linked Fmoc -Wang bound Fmoc-L- instead of L-leucine
Examples except starting with asparagine (Trt) and using benzofuran-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 28 (a) -28 (d). MS [M + H] ⁺ 505.4.

Example 38 5-benzofuran-2-yl-2- (2-carbamoyl-ethyl) -1- [1- (
Preparation of 4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Examples except starting with glutamine (Trt) and using benzofuran-2-carboxyaldecht instead of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 28 (a) -28 (d). MS [M + H] ⁺ 518.4.

Example 39 5-Benzofuran-2-yl-2- (3H-imidazol-4-ylmethyl)-
1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2
Production of 1,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Examples except starting with histidine (Trt) and using benzofuran-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 28 (a) -28 (d). MS [M + H] ⁺ 528.4.

Example 40 Preparation of 5-benzofuran-2-yl-2-hydroxymethyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Wang conjugated Fmoc -Wang bound Fmoc-L- instead of L-leucine
Examples except starting with serine (tBu) and using benzofuran-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 28 (a) -28 (d). MS [M + H] ⁺ 478.4.

Example 41 Preparation of 2-isobutyl-1- (1-naphthalen-1-yl-methanoyl) -5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid of 3,4-dichlorobenzoyl chloride The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 1-naphthoyl chloride was used instead. MS [M + H] ⁺ 452.5.

Example 42 Preparation of 5-furan-2-yl-2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Thiophene-2- According to the method of Examples 28 (a) -28 (d), except that furan-2-carboxaldehyde was used instead of carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid. MS [M + H] ⁺ 454.4.

Example 43 5- [5- (4-chloro-phenyl) -furan-2-yl] -2-isobutyl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
Preparation of 4-dicarboxylic acid 5- (4-chloro-phenyl) -furan-2-carboxaldehyde was used instead of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of Example 28 (a) -28 (d) except using chloride. MS [M + H] ⁺ 564.9.

Example 44 5- [5- (4-chloro-phenyl) -furan-2-yl] -2-isobutyl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
Preparation of 4-dicarboxylic acid Example 28 (except that thiazole-2-carboxaldehyde was used in place of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride. a) -28 (d
The title compound was prepared as a solid according to the method of 1.). MS [M + H] ⁺ 471.
4.

Example 45 Preparation of 2- (2-carbamoyl-ethyl) -5-furan-2-yl-1- (1-o-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Wang linked Fmoc- Wang-bound Fmoc-L- instead of L-leucine
Example 28 (except starting with glutamine (Trt) and using furan-2-carboxaldehyde in place of thiophene-2-carboxaldehyde and o-toluoyl chloride in place of 3,4-dichlorobenzoyl chloride. a) -2
The title compound was prepared as a solid according to the method of 8 (d). MS [M + H] ⁺
415.4.

Example 46 Preparation of 5-furan-2-yl-2-hydroxymethyl-1- (1-o-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Substitute for Wang-conjugated Fmoc-L-leucine Wang binding to Fmoc-L-
Example 28 (except starting with serine (tBu) and using furan-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and o-toluoyl chloride instead of 3,4-dichlorobenzoyl chloride. a) -28 (
The title compound was prepared as a solid according to the method of d). MS [M + H] ⁺ 37
4.3.

Example 47 5-furan-2-yl-2- (1H-imidazol-4-ylmethyl) -1- (
Preparation of 1-o-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except starting with histidine (Trt) and using furan-2-carboxaldehyde in place of thiophene-2-carboxaldehyde and o-toluoyl chloride in place of 3,4-dichlorobenzoyl chloride. a) -2
The title compound was prepared as a solid according to the method of 8 (d). MS [M + H] ⁺
424.4.

Example 48 2- (2-carbamoyl-ethyl) -5-thiazol-2-yl-1- (1-o
-Tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid preparation Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except starting with glutamine (Trt) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and o-toluoyl chloride instead of 3,4-dichlorobenzoyl chloride. a)
The title compound was prepared as a solid according to the method of -28 (d). MS [M + H
] ⁺ 432.4.

Example 49 2-Hydroxymethyl-5-thiazol-2-yl-1- (1-o-tolyl-
Preparation of methanoyl) -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except starting with serine (tBu) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and o-toluoyl chloride instead of 3,4-dichlorobenzoyl chloride. a) -2
The title compound was prepared as a solid according to the method of 8 (d). MS [M + H] ⁺
391.4.

Example 50 2- (1H-Imidazol-4-ylmethyl) -5-thiazol-2-yl-1
Preparation of-(1-o-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except starting with histidine (Trt) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and o-toluoyl chloride instead of 3,4-dichlorobenzoyl chloride. a)
The title compound was prepared as a solid according to the method of -28 (d). MS [M + H
] ⁺ 441.4.

Example 51 2- (2-carbamoyl-ethyl) -5- [5- (4-chloro-phenyl) -furan-2-yl] -1- (1-o-tolyl-methanoyl) -pyrrolidine- Production of 2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with glutamine (Trt), substituting 5- (4-chloro-phenyl) -furan-2-carboxaldehyde for thiophene-2-carboxaldehyde,
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except o-toluoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 525.9.

Example 52 5- [5- (4-Chloro-phenyl) -furan-2-yl] -2-hydroxymethyl-1- (1-o-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic Production of acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with serine (tBu) and substituting 5- (4-chloro-phenyl) -furan-2-carboxaldehyde for thiophene-2-carboxaldehyde, 3,
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except o-toluoyl chloride was used instead of 4-dichlorobenzoyl chloride. MS [M + H] ⁺ 484.9.

Example 53 5- [5- (4-chloro-phenyl) -furan-2-yl] -2- (1H-imidazol-4-ylmethyl) -1- (1-o-tolyl-methanoyl)- Pyrrolidine-
Production of 2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with histidine (Trt) and substituting 5- (4-chloro-phenyl) -furan-2-carboxaldehyde for thiophene-2-carboxaldehyde,
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except o-toluoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 534.9.

Example 54 2- (2-carbamoyl-ethyl) -5-thiophen-2-yl-1- (1-o
-Tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid preparation Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except starting with glutamine (Trt) and using o-toluoyl chloride instead of 3,4-dichlorobenzoyl chloride. . MS [M + H] ⁺ 431.4.

Example 55 2-Hydroxymethyl-5-thiophen-2-yl-1- (1-o-tolyl-
Preparation of methanoyl) -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with serine (tBu), o instead of 3,4-dichlorobenzoyl chloride
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that toluoyl chloride was used. MS [M + H] ⁺ 390.4.

Example 56 2- (1H-imidazol-4-ylmethyl) -5-thiophen-2-yl-1
Preparation of-(1-o-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except starting with histidine (Trt) and using o-toluoyl chloride instead of 3,4-dichlorobenzoyl chloride. . MS [M + H] ⁺ 440.4.

Example 57 1- [1- (4-chloro-phenyl) -methanoyl] -5-furan-2-yl-2
Preparation of-(1H-imidazol-4-ylmethyl) -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except that starting with histidine (Trt), furan-2-carboxaldehyde was used instead of thiophene-2-carboxaldehyde and 4-chlorobenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. a
) -28 (d), the title compound was prepared as a solid. MS [M +
H] ⁺ 444.8.

Example 58 Preparation of 2- (2-carbamoyl-ethyl) -1- [1- (4-chloro-phenyl) -methanoyl] -5-thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 except starting with glutamine (Trt) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-chlorobenzoyl chloride instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of (a) -28 (d). MS [
M + H] ⁺ 452.8.

Example 59 1- [1- (4-chloro-phenyl) -methanoyl] -2-hydroxymethyl-5
-Preparation of thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except that starting with serine (tBu) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-chlorobenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. a
) -28 (d), the title compound was prepared as a solid. MS [M +
H] ⁺ 411.8.

Example 60 1- [1- (4-chloro-phenyl) -methanoyl] -2- (1H-imidazol-4-ylmethyl) -5-thiazol-2-yl-pyrrolidin-2,4-dicarboxylic acid Preparation of Wang-bound Fmoc-L-leucine instead of Wang-bound Fmoc-L-
Example 28 except starting with histidine (Trt) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-chlorobenzoyl chloride instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of (a) -28 (d). MS [
M + H] ⁺ 461.8.

Example 61 5- [5- (4-chloro-phenyl) -furan-2-yl] -1- [1- (4-chloro-phenyl) -methanoyl] -2-hydroxymethyl-pyrrolidine-2 Production of 1,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with serine (tBu) and substituting 5- (4-chloro-phenyl) -furan-2-carboxaldehyde for thiophene-2-carboxaldehyde, 3,
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except 4-chlorobenzoyl chloride was used in place of 4-dichlorobenzoyl chloride. MS [M + H] ⁺ 505.3.

Example 62 Preparation of 2- (2-carbamoyl-ethyl) -1- [1- (4-chloro-phenyl) -methanoyl] -5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Examples 28 (a) -28 (d) except starting with glutamine (Trt) and using 4-chlorobenzoyl chloride instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of. MS [M + H] ⁺ 451.8
.

Example 63 5-furan-2-yl-2- (1H-imidazol-4-ylmethyl) -1- [
1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-
Preparation of dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Examples except starting with histidine (Trt) and using furan-2-carboxaldehyde in place of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride in place of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 28 (a) -28 (d). MS [M + H] ⁺ 478.3.

Example 64 2- (2-carbamoyl-ethyl) -5-thiazol-2-yl-1- [1- (4
Preparation of -trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Examples except starting with glutamine (Trt) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 28 (a) -28 (d). MS [M + H] ⁺ 486.4.

Example 65 Preparation of 2-hydroxymethyl-5-thiazol-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Wang linked Fmoc -Wang bound Fmoc-L- instead of L-leucine
Examples except starting with serine (tBu) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 28 (a) -28 (d). MS [M + H] ⁺ 445.3.

Example 66 2- (1H-imidazol-4-ylmethyl) -5-thiazol-2-yl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
Preparation of 4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example except starting with histidine (Trt) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 4-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 28 (a) -28 (d). MS [M + H] ⁺ 495.4.

Example 67 5- [5- (4-Chloro-phenyl) -furan-2-yl] -2-hydroxymethyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine -Preparation of 2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with serine (tBu) and substituting 5- (4-chloro-phenyl) -furan-2-carboxaldehyde for thiophene-2-carboxaldehyde, 3,
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except 4-trifluoromethylbenzoyl chloride was used in place of 4-dichlorobenzoyl chloride. MS [M + H] ⁺ 538.8.

Example 68 5- [5- (4-chloro-phenyl) -furan-2-yl] -2- (1H-imidazol-4-ylmethyl) -1- [1- (4-trifluoromethyl- Preparation of (phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with histidine (Trt) and substituting 5- (4-chloro-phenyl) -furan-2-carboxaldehyde for thiophene-2-carboxaldehyde,
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 4-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 588.9.

Example 69 Preparation of 2- (2-carbamoyl-ethyl) -1- (1-naphthalen-1-yl-methanoyl) -5-thiazol-2-yl-pyrrolidin-2,4-dicarboxylic acid Wang linkage Instead of Fmoc-L-leucine, Wang-bound Fmoc-L-
Example 28 (except starting with glutamine (Trt) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 1-naphthoyl chloride instead of 3,4-dichlorobenzoyl chloride. a)
The title compound was prepared as a solid according to the method of -28 (d). MS [M + H
] ⁺ 468.5.

Example 70 2-Hydroxymethyl-1- (1-naphthalen-1-yl-methanoyl) -5-
Preparation of thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except that starting with serine (tBu) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 1-naphthoyl chloride instead of 3,4-dichlorobenzoyl chloride. a) -2
The title compound was prepared as a solid according to the method of 8 (d). MS [M + H] ⁺
427.4.

Example 71 Preparation of 2- (1H-imidazol-4-ylmethyl) -1- (1-naphthalen-1-yl-methanoyl) -5-thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except starting with histidine (Trt) and using thiazole-2-carboxaldehyde instead of thiophene-2-carboxaldehyde and 1-naphthoyl chloride instead of 3,4-dichlorobenzoyl chloride. a)
The title compound was prepared as a solid according to the method of -28 (d). MS [M + H
] ⁺ 477.5.

Example 72 2- (2-carbamoyl-ethyl) -5- [5- (4-chloro-phenyl) -furan-2-yl] -1- (1-naphthalen-1-yl-methanoyl)- Pyrrolidine-
Production of 2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with glutamine (Trt), substituting 5- (4-chloro-phenyl) -furan-2-carboxaldehyde for thiophene-2-carboxaldehyde,
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 1-naphthoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 561.9.

Example 73 5- [5- (4-Chloro-phenyl) -furan-2-yl] -2- (1H-imidazol-4-ylmethyl) -1- (1-naphthalen-1-yl-methanoyl ) -Preparation of pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with histidine (Trt) and substituting 5- (4-chloro-phenyl) -furan-2-carboxaldehyde for thiophene-2-carboxaldehyde,
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 1-naphthoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 570.9.

Example 74 Preparation of 2- (2-carbamoyl-ethyl) -1- (1-naphthalen-1-yl-methanoyl) -5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid Wang linkage Instead of Fmoc-L-leucine, Wang-bound Fmoc-L-
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except starting with glutamine (Trt) and using 1-naphthoyl chloride instead of 3,4-dichlorobenzoyl chloride. . MS [M + H] ⁺ 467.5.

Example 75 2-Hydroxymethyl-1- (1-naphthalen-1-yl-methanoyl) -5-
Preparation of thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with serine (tBu), 1 instead of 3,4-dichlorobenzoyl chloride
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that naphthoyl chloride was used. MS [M + H] ⁺ 426.4.

Example 76 Preparation of 2- (1H-imidazol-4-ylmethyl) -1- (1-naphthalen-1-yl-methanoyl) -5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except starting with histidine (Trt) and using 1-naphthoyl chloride instead of 3,4-dichlorobenzoyl chloride. . MS [M + H] ⁺ 476.5.

Example 77 Preparation of 2-isobutyl-5-thiophen-3-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Thiophene-2- Example 28 (a) -28 (d) except that thiophen-3-carboxaldehyde was used in place of carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of 1.). MS [M + H] ⁺ 470.
4.

Example 78 Preparation of 5-furan-3-yl-2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Thiophene-2- According to the method of Examples 28 (a) -28 (d) except that furan-3-carboxaldehyde was used in place of carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid. MS [M + H] ⁺ 454.4.

Example 79 Preparation of 2-isobutyl-5-pyridin-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Thiophene-2- Examples 28 (a) -28 (d) except that pyridine-2-carboxaldehyde was used instead of carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of. MS [M + H] ⁺ 465.4
.

Example 80 5- (5-Ethyl-furan-2-yl) -2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Preparation of 5-Ethyl-furan-2-instead of thiophene-2-carboxaldehyde
Example 28 (a)-except that carboxaldehyde was used and 4-trifluoromethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of 28 (d). MS [M + H] ⁺ 482.4.

Example 81 Preparation of 2-isobutyl-5-thiazol-2-yl-1- (1-p-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Thiazole instead of thiophene-2-carboxaldehyde 2-carboxaldehyde was used according to the method of Examples 28 (a) -28 (d) except that p-toluoyl chloride was used instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid. MS [M + H] ⁺ 417.4.

Example 82 Preparation of 5-benzofuran-2-yl-2-isobutyl-1- (1-p-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Benzofuran instead of thiophene-2-carboxaldehyde The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 2-carboxaldehyde was used and p-toluoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. . MS [M + H] ⁺ 450.5.

Example 83 1- [1- (4-tert-butyl-phenyl) -methanoyl] -2-isobutyl-5
Preparation of -thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid Examples 28 (a) -28 (d) except that 4-t-butylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of. MS [M + H] ⁺ 458.5.

Example 84 Preparation of 1- [1- (4-ethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 3,4-dichlorobenzoyl The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except 4-ethylbenzoyl chloride was used instead of chloride. MS [M + H] ⁺ 430.5.

Example 85 Preparation of 1- (1-biphenyl-4-yl-methanoyl) -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid of 3,4-dichlorobenzoyl chloride The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except using 4-biphenylcarbonyl chloride instead. MS [M + H] ⁺ 478.5.

Example 86 Preparation of 1- [1- (3-chloro-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 3,4-dichlorobenzoyl The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except 3-chlorobenzoyl chloride was used in place of chloride. MS [M + H] ⁺ 436.9.

Example 87 Preparation of 1- [1- (3-Bromo-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 3,4-dichlorobenzoyl The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 3-bromobenzoyl chloride was used instead of chloride. MS [M + H] ⁺ 481.3.

Example 88 Preparation of 2-isobutyl-5-thiophen-2-yl-1- (1-m-tolyl-methanoyl) -pyrrolidine-2,4-dicarboxylic acid Instead of 3,4-dichlorobenzoyl chloride The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that m-toluoyl chloride was used. MS [M + H] ⁺ 416.5.

Example 89 1- [1- (3,4-difluoro-phenyl) -methanoyl] -2-isobutyl-
Preparation of 5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid Examples 28 (a) -28 (d) except that 3,4-difluorobenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 1.). MS [M + H] ⁺ 438.4.

Example 90 Preparation of 1- [1- (4-fluoro-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 3,4-dichlorobenzoyl The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 4-fluorobenzoyl chloride was used instead of chloride. MS [M + H] ⁺ 420.4.

Example 91 5-furan-2-yl-2-isobutyl-1- (1-p-tolyl-methanoyl)
-Preparation of pyrrolidine-2,4-dicarboxylic acid Carried out except that furan-2-carboxaldehyde was used instead of thiophene-2-carboxaldehyde and p-toluoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d). MS [M + H] ⁺ 400.4.

Example 92 1- [1- (4-chloro-phenyl) -methanoyl] -2-hydroxymethyl-5
-Preparation of thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with serine (tBu), 4 instead of 3,4-dichlorobenzoyl chloride
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except using -chlorobenzoyl chloride. MS [M + H] ⁺ 410.8.

Example 93 Preparation of 2-hydroxymethyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Wang linked Fmoc -Wang bound Fmoc-L- instead of L-leucine
Starting with serine (tBu), 4 instead of 3,4-dichlorobenzoyl chloride
Example 28 (a) -2 except that -trifluoromethylbenzoyl chloride was used
The title compound was prepared as a solid according to the method of 8 (d). MS [M + H] ⁺
444.3.

Example 94 2-carbamoylmethyl-1- (1-naphthalen-1-yl-methanoyl) -5
-Preparation of thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Example 28 (except starting with asparagine (Trt) and using thiazole-2-carboxaldehyde in place of thiophene-2-carboxaldehyde and 1-naphthoyl chloride in place of 3,4-dichlorobenzoyl chloride. a
) -28 (d), the title compound was prepared as a solid. MS [M +
H] ⁺ 454.4.

Example 95 Preparation of 1- [1- (bis-trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 3,4- The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 2,5-bistrifluoromethylbenzoyl chloride was used instead of dichlorobenzoyl chloride. MS [M + H] ⁺ 538.4.

Example 96 Preparation of 1- [1- (bis-trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 3,4- The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 3,5-bistrifluoromethylbenzoyl chloride was used instead of dichlorobenzoyl chloride. MS [M + H] ⁺ 538.4.

Example 97 Preparation of 2-isobutyl-5-thiazol-2-yl-1- [1- (3-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Thiophene-2- Examples 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used instead of carboxaldehyde and 3-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of 1.). MS [M + H] ⁺ 471.
4.

Example 98 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
-Preparation of thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid The method of Examples 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used instead of thiophene-2-carboxaldehyde The title compound was prepared as a solid according to. MS [M + H] ⁺ 472.4.

Example 99 Preparation of 1- [1- (3-Bromo-phenyl) -methanoyl] -2-isobutyl-5-thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid Thiophene-2-carboxaldehyde According to the method of Example 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used in place of 3,4-dichlorobenzoyl chloride and 3-bromobenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride. Prepared as a solid. MS [M + H] ⁺ 482.3.

Example 100 Preparation of 1- [1- (4-Ethyl-phenyl) -methanoyl] -2-isobutyl-5-thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid Thiophene-2-carboxaldehyde According to the method of Example 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used in place of, and 4-ethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride. Prepared as a solid. MS [M + H] ⁺ 431.5.

Example 101 1- [1- (4-tert-butyl-phenyl) -methanoyl] -2-isobutyl-5
-Thiazol-2-yl-pyrrolidine-2,4-dicarboxylic acid preparation Thiazol-2-carboxaldehyde was used instead of thiophene-2-carboxaldehyde and 4-t- was used instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that butylbenzoyl chloride was used. MS [M + H] ⁺ 459.5.

Example 102 Preparation of 5-furan-2-yl-2-isobutyl-1- [1- (3-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Thiophene-2- According to the method of Examples 28 (a) -28 (d) except furan-2-carboxaldehyde was used instead of carboxaldehyde and 3-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid. MS [M + H] ⁺ 454.4.

Example 103 Preparation of 1- [1- (3,4-dichloro-phenyl) -methanoyl] -5-furan-2-yl-2-isobutyl-pyrrolidine-2,4-dicarboxylic acid Thiophene-2- The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except furan-2-carboxaldehyde was used instead of carboxaldehyde. MS [M + H] ⁺ 455.3.

Example 104 1- [1- (3-Bromo-phenyl) -methanoyl] -5-furan-2-yl-2
-Preparation of isobutyl-pyrrolidine-2,4-dicarboxylic acid except that furan-2-carboxaldehyde was used instead of thiophene-2-carboxaldehyde and 3-bromobenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. Produced the title compound as a solid according to the method of Example 28 (a) -28 (d). MS [M + H] ⁺ 465.3.

Example 105 Preparation of 5-benzofuran-2-yl-2-isobutyl-1- [1- (3-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid Thiophene-2- Example 28 (a) -28 (except that benzofuran-2-carboxaldehyde was used in place of carboxaldehyde and 3-trifluoromethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of d). MS [M + H] ⁺ 50
4.4.

Example 106 Preparation of 5-benzofuran-2-yl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid Thiophene-2- According to the method of Examples 28 (a) -28 (d) except using benzofuran-2-carboxaldehyde instead of carboxaldehyde.
The title compound was prepared as a solid. MS [M + H] ⁺ 505.3.

Example 107 Preparation of 5-benzofuran-2-yl-1- [1- (3-bromo-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid Thiophene-2-carboxaldehyde Was replaced with benzofuran-2-carboxaldehyde and the title compound was prepared according to the method of Example 28 (a) -28 (d) except that 3-bromobenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. Prepared as a solid. MS [M + H] ⁺ 515.3.

Example 108 Preparation of 5-benzofuran-2-yl-1- [1- (4-tert-butyl-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid Thiophene-2- Benzofuran-2-carboxaldehyde was used instead of carboxaldehyde and 4-t was used instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that -butylbenzoyl chloride was used. MS [M + H] ⁺ 492.5.

Example 109 5-Benzofuran-2-yl-4-carbamoyl-2-isobutyl-1- [1
Preparation of-(4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
According to the method of Examples 28 (a) -28 (d) except that benzofuran-2-carboxaldehyde was used instead of carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid. MS [M + H] ⁺ 503.4.

Example 110 4-carbamoyl-5-furan-2-yl-2-isobutyl-1- [1- (4-
Preparation of trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
Furan-2-carboxaldehyde was used instead of carboxaldehyde.
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 4-trifluoromethylbenzoyl chloride was used instead of 4,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 453.4.

Example 111 4-carbamoyl-2-isobutyl-5-thiazol-2-yl-1- [1- (
Preparation of 4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
According to the method of Examples 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used instead of carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. ,
The title compound was prepared as a solid. MS [M + H] ⁺ 470.4.

Example 112 4-carbamoyl-2-isobutyl-5-thiazol-2-yl-1- [1- (
Preparation of 3-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
According to the method of Examples 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used instead of carboxaldehyde and 3-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. ,
The title compound was prepared as a solid. MS [M + H] ⁺ 470.4.

Example 113 4-carbamoyl-1- [1- (3,4-dichloro-phenyl) -methanoyl]-
Preparation of 2-isobutyl-5-thiazol-2-yl-pyrrolidine-2-carboxylic acid Using acrylamide in place of tert-butyl acrylate, thiophene-2-
The title compound was prepared as a solid according to the method of Example 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used instead of carboxaldehyde. MS [M + H] ⁺ 471.3.

Example 114 Preparation of 1- [1- (3-Bromo-phenyl) -methanoyl] -4-carbamoyl-2-isobutyl-5-thiazol-2-yl-pyrrolidine-2-carboxylic acid Acrylic acid tert- Using acrylamide instead of butyl, thiophene-2-
According to the method of Example 28 (a) -28 (d), except that thiazole-2-carboxaldehyde was used instead of carboxaldehyde, and 3-bromobenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The compound was prepared as a solid. MS [M + H] ⁺ 481.3.

Example 115 Preparation of 4-carbamoyl-1- [1- (4-ethyl-phenyl) -methanoyl] -2-isobutyl-5-thiazol-2-yl-pyrrolidine-2-carboxylic acid Acrylic acid tert- Using acrylamide instead of butyl, thiophene-2-
According to the method of Example 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used in place of carboxaldehyde and 4-ethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride. The compound was prepared as a solid. MS [M + H] ⁺ 430.5.

Example 116 1- [1- (4-tert-butyl-phenyl) -methanoyl] -4-carbamoyl-
Preparation of 2-isobutyl-5-thiazol-2-yl-pyrrolidine-2-carboxylic acid Using acrylamide in place of tert-butyl acrylate, thiophene-2-
According to the method of Examples 28 (a) -28 (d) except that thiazole-2-carboxaldehyde was used instead of carboxaldehyde and 4-tert-butylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid. MS [M + H] ⁺ 458.5.

Example 117 4-carbamoyl-2-isobutyl-5-thiophen-3-yl-1- [1- (
Preparation of 4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
According to the method of Examples 28 (a) -28 (d) except that thiophene-3-carboxaldehyde was used instead of carboxaldehyde and 4-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. ,
The title compound was prepared as a solid. MS [M + H] ⁺ 469.4.

Example 118 4-carbamoyl-5-furan-3-yl-2-isobutyl-1- [1- (4-
Preparation of trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
Furan-3-carboxaldehyde was used instead of carboxaldehyde.
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that 4-trifluoromethylbenzoyl chloride was used instead of 4,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 453.4.

Example 119 4-carbamoyl-2- (1H-imidazol-4-ylmethyl) -5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl]
-Production of pyrrolidine-2-carboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Examples 28 (a) -28 except starting with histidine (Trt) and using acrylamide instead of tert-butyl acrylate and using 4-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of (d). MS [M + H] ⁺ 493.4.

Example 120 4-carbamoyl-2-isobutyl-5-thiophen-2-yl-1- [1- (
Preparation of 3-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Acrylamide was used instead of tert-butyl acrylate, and 3-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of Example 28 (a) -28 (d) except that it was used. MS [M + H] ⁺ 469.4.

Example 121 4-carbamoyl-2-isobutyl-5-thiophen-2-yl-1- [1- (
Preparation of 3-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Example 28 except that acrylamide was used instead of tert-butyl acrylate.
The title compound was prepared as a solid according to the method of (a) -28 (d). MS [
M + H] ⁺ 469.4.

Example 122 Preparation of 1- [1- (3-Bromo-phenyl) -methanoyl] -4-carbamoyl-2-isobutyl-5-thiophen-2-yl-pyrrolidine-2-carboxylic acid Acrylic acid tert- Prepare the title compound as a solid according to the method of Example 28 (a) -28 (d) except that acrylamide was used instead of butyl and 3-bromomethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. did. MS [M + H] ⁺ 480.3.

Example 123 4-carbamoyl-5-furan-2-yl-2-isobutyl-1- [1- (3-
Preparation of trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
Furan-2-carboxaldehyde was used instead of carboxaldehyde.
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d), except that 3-trifluoromethylbenzoyl chloride was used instead of 4,4-dichlorobenzoyl chloride. MS [M + H] ⁺ 453.4.

Example 124 Preparation of 4-carbamoyl-2-isobutyl-5- (1-methyl-1H-imidazol-2-yl) -1- (1-m-tolyl-methanoyl) -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
Examples 28 (a) -28 (d) except that 1-methyl-1H-imidazole-2-carboxaldehyde was used in place of carboxaldehyde and p-toluoyl chloride was used in place of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 1.). MS [M + H] ⁺ 413.4.

Example 126 4-carbamoyl-1- [1- (4-ethyl-phenyl) -methanoyl] -2-isobutyl-5- (1-methyl-1H-imidazol-2-yl) -pyrrolidine-2
-Production of carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
Examples 28 (a) -28 (d) except that 1-methyl-1H-imidazole-2-carboxaldehyde was used in place of carboxaldehyde and 4-ethylbenzoyl chloride was used in place of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 1.). MS [M + H] ⁺ 427.5.

Example 127 1- [1- (4-tert-butyl-phenyl) -methanoyl] -4-carbamoyl-
Preparation of 2-isobutyl-5- (1-methyl-1H-imidazol-2-yl) -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
1-Methyl-1H-imidazole-2-carboxaldehyde was used instead of carboxaldehyde and 4-ter instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that t-butylbenzoyl chloride was used. MS [M + H] ⁺ 455.5.

Example 128 4-carbamoyl-1- [1- (3,4-difluoro-phenyl) -methanoyl]
Preparation of 2-isobutyl-5- (1-methyl-1H-imidazol-2-yl) -pyrrolidine-2-carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
1-Methyl-1H-imidazole-2-carboxaldehyde was used instead of carboxaldehyde and 3,4-dichlorobenzoyl chloride was used instead of 3,4-
The title compound was prepared as a solid according to the method of Examples 28 (a) -28 (d) except that difluorobenzoyl chloride was used. MS [M + H] ⁺ 435.4.

Example 129 1- [1- (bis-trifluoromethyl-phenyl) -methanoyl] -4-carbamoyl-2-isobutyl-5- (1-methyl-1H-imidazol-2-yl)-
Preparation of Pyrrolidine-2-carboxylic acid Thirophene-2-
1-Methyl-1H-imidazole-2-carboxaldehyde was used instead of carboxaldehyde, and 2,5-dichlorobenzoyl chloride was used instead of 2,5-dichlorobenzoyl chloride.
Example 28 (a)-except that bistrifluoromethylbenzoyl chloride was used.
The title compound was prepared as a solid according to the method of 28 (d). MS [M + H] ⁺ 535.4.

Example 130 4-carbamoyl-2-isobutyl-5- (1-methyl-1H-imidazol-2-yl) -1- (1-naphthalen-1-yl-methanoyl) -pyrrolidine-2
-Production of carboxylic acid Using acrylamide instead of tert-butyl acrylate, thiophene-2-
Examples 28 (a) -28 (d) except that 1-methyl-1H-imidazole-2-carboxaldehyde was used instead of carboxaldehyde and 1-naphthoyl chloride was used instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of 1.). MS [M + H] ⁺ 449.5.

Example 131 4-carbamoyl-2- (1H-imidazol-4-ylmethyl) -5-thiophen-2-yl-1- [1- (3-trifluoromethyl-phenyl) -methanoyl]
-Production of pyrrolidine-2-carboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Examples 28 (a) -28 except starting with histidine (Trt) and using acrylamide instead of tert-butyl acrylate and 3-trifluoromethylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of (d). MS [M + H] ⁺ 493.4.

Example 132 1- [1- (4-tert-butyl-phenyl) -methanoyl] -4-carbamoyl-
Preparation of 2- (1H-imidazol-4-ylmethyl) -5-thiophen-2-yl-pyrrolidin-2-carboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Examples 28 (a) -28 except starting with histidine (Trt) and using acrylamide instead of tert-butyl acrylate and using 4-tert-butylbenzoyl chloride instead of 3,4-dichlorobenzoyl chloride. The title compound was prepared as a solid according to the method of (d). MS [M + H] ⁺ 481.5.

Example 133 4-carbamoyl-2- (1H-imidazol-4-ylmethyl) -5-thiazol-2-yl-1- [1- (3-trifluoromethyl-phenyl) -methanoyl]
-Production of pyrrolidine-2-carboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with histidine (Trt), using acrylamide instead of tert-butyl acrylate and thiazole-2 instead of thiophene-2-carboxaldehyde.
Example 28 (a) except that -carboxaldehyde was used and 3-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of -28 (d). MS [M + H
] ⁺ 494.4.

Example 134 4-carbamoyl-2- (1H-imidazol-4-ylmethyl) -5-thiazol-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl]
-Production of pyrrolidine-2-carboxylic acid Wang-bound Fmoc-L- instead of Wang-bound Fmoc-L-leucine
Starting with histidine (Trt), using acrylamide instead of tert-butyl acrylate and thiazole-2 instead of thiophene-2-carboxaldehyde.
Example 28 (a) except that -carboxaldehyde was used and 4-trifluoromethylbenzoyl chloride was used instead of 3,4-dichlorobenzoyl chloride.
The title compound was prepared as a solid according to the method of -28 (d). MS [M + H
] ⁺ 494.4.

Alternative Synthetic Methods for the Compound of Example 15 According to Scheme 3 and Examples 135-135
Methods of synthesizing the compound of 147 are also included in the invention.

[0164]

[Chemical 5]

Example 15 (Alternative Preparation According to Scheme 3) 1- [1- (4-Trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidine-2 Preparation of 1,4-dicarboxylic acid a) 4-Methyl-2-[(thiophen-2-ylmethylene) -amino] -pentanoic acid t-butyl ester Leucine t-butyl ester (10 g) in a stirred solution in toluene (100 mL). Thiophene-2-carboxaldehyde (5.0 mL) is added and the mixture is heated to 90 ° C. for 2 hours. The mixture was cooled, washed with water, dried over magnesium sulphate, filtered and evaporated to an oil (14.5g).

B) 2-Isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 2,4-di-tert-butyl ester Compound 135 (a) is dissolved in acetonitrile (300 mL) at room temperature. It was stirred at. Tert-Butyl acrylate (2 eq, 15 mL) was added, followed by silver acetate (
1.5 eq, 12.92 g) and triethylamine (1.0 eq, 7.2 mL) were added. The mixture was stirred for 16 hours and poured into 250 mL saturated ammonium chloride. The mixture was extracted 3 times with diethyl ether. The organic extracts were combined, washed with water, dried over magnesium sulphate, filtered and evaporated to an oil.

C) 1- [1- (4-Trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 2,4-
Di-tert-butyl ester A part of compound 135 (b) (0.55 g) was added to tetrahydrofuran (2.5 mL).
And was treated with triethylamine (1.1 eq, 0.2 mL) and 4-trifluoromethylbenzoyl chloride (1.1 eq, 0.2 mL). 1 of the mixture
Stir for 4 hours. The mixture was diluted with dichloromethane (10 mL) and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to give a solid. The crude solid was purified by preparative HPLC to give the title compound as a white solid.

D) 1- [1- (4-Trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid Compound 135 (c) is neat. Stir in trifluoroacetic acid for 1 h, dilute with dichloroethane and evaporate to give a tan solid that is chromatographed using Gilson reverse phase HPLC to give the desired compound as a solid. Obtained.
MS [M + H] ⁺ 470.1.

Example 135 Preparation of 1- [1- (4-cyano-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 4-trifluoromethylbenzoyl The title compound was prepared as a solid according to the method of Scheme 3 except that 4-cyanobenzoyl chloride was used in place of chloride. MS [M + H] ⁺ 427.1.

Example 136 Preparation of 1- [1- (4-nitro-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 4-trifluoromethylbenzoyl The title compound was prepared as a solid according to the method of Scheme 3 except 4-nitrobenzoyl chloride was used instead of chloride. MS [M + H] ⁺ 447.0.

Example 137 Preparation of 2-isobutyl-5-thiophen-2-yl-1- (1-thiophen-2-yl-methanoyl) pyrrolidine-2,4-dicarboxylic acid Substitute for 4-trifluoromethylbenzoyl chloride The title compound was prepared as a solid according to the method of Scheme 3 except that thiophene-2-carbonyl chloride was used in. MS [M + H] ⁺ 408.2.

Example 138 Preparation of 5-sec-Butyl-2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Acrylic acid Using methyl acrylate instead of t-butyl, thiophene-2-
The title compound was prepared as a solid according to the method of Scheme 3 except that isobutyraldehyde was used instead of carboxaldehyde. MS [M + H] ⁺ 459.
1.

Example 139 Preparation of 1- [1- (4-cyano-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 4-methyl ester Acrylic acid The title compound was prepared as a solid according to the method of Scheme 3 except that methyl acrylate was used in place of t-butyl and 4-cyanobenzoyl chloride was used in place of 4-trifluoromethylbenzoyl chloride. MS [M +
H] ⁺ 441.2.

Example 140 Preparation of 1- [1- (4-Nitro-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 4-methyl ester Acrylic acid The title compound was prepared as a solid according to the method of Scheme 3 except that methyl acrylate was used in place of t-butyl and 4-nitrobenzoyl chloride was used in place of 4-trifluoromethylbenzoyl chloride. MS [M +
H] ⁺ 461.2.

Example 141 1- [1- (4-pyridyl) -methanoyl] -2-isobutyl-5-thiophene-
Preparation of 2-yl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester Use methyl acrylate instead of t-butyl acrylate and use 4-aza-benzoyl chloride instead of 4-trifluoromethylbenzoyl chloride. The title compound was prepared as a solid according to the method of Scheme 3 except that MS [M +
H] ⁺ 416.1.

Example 142 Preparation of 1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 2-methyl ester The title compound was prepared as a solid according to the method of Scheme 3 except that leucine methyl ester was used instead of leucine-t-butyl ester. MS [M +
H] ⁺ 484.2.

Example 143 Preparation of 1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 2-benzyl ester The title compound was prepared as a solid according to the method of Scheme 3 except that leucine benzyl ester was used instead of leucine-t-butyl ester. MS [M
+ H] ⁺ 560.2.

Example 144 1- [1- (4-Trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 2,4-dimethyl ester Preparation of The title compound was prepared as a solid according to the method of Scheme 3 except that leucine methyl ester was used instead of leucine-t-butyl ester and methyl acrylate was used instead of t-butyl acrylate. MS [M + H] ⁺ 498.1.

Example 145 Preparation of 1- [1- (3-trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid 4-trifluoro The title compound was prepared as a solid according to the method of Scheme 3 except 3-trifluoromethylbenzoyl chloride was used in place of methylbenzoyl chloride. MS [M + H] ⁺ 470.2.

Example 146 Preparation of 1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5-methyl-pyrrolidine-2,4-dicarboxylic acid Substitute for thiophene-2-carboxaldehyde The title compound was prepared as a solid according to the method of Scheme 3 except that acetaldehyde was used in. MS 4
02.4 [M + H] ⁺ .

Example 147 Preparation of 1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -2-isobutyl-5- (2-methylethyl) -pyrrolidine-2,4-dicarboxylic acid Thiophene-2 -The title compound was prepared as a solid according to the method of Scheme 3 except that isobutyraldehyde was used instead of carboxaldehyde. MS
430.4 [M + H] ⁺ .

To use a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is usually used as a pharmaceutical composition in accordance with standard pharmaceutical practice. Be prescribed.

The licands of the present invention can be administered by a variety of routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal. . For systemic administration, oral administration is preferred. For oral administration, the compounds can be formulated in conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs and concentrated drops.

Alternatively, injection (parenteral administration), such as intramuscular injection, intravenous injection, intraperitoneal injection, and subcutaneous injection, can be used. For injections, the compounds of the invention are preferably formulated in solution in a physiologically compatible buffer or solution such as saline, Hank's solution or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be prepared.

Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, surfactants can be used to enhance penetration. Transmucosal administration can be accomplished, for example, via a nasal spray, rectal suppository, or vaginal suppository.

For topical administration, the compounds of the present invention may be formulated in ointments, gels or creams as is generally known in the art.

Dosages of various compounds will vary depending on the compound (IC ₅₀ ) potency, (EC ₅₀ ) potency and biological half-life (of the compound), patient age, size and weight, and the disease or disorder associated with the patient. Can be determined by a standard method in consideration of factors such as The importance of these and other factors to consider is known to those of skill in the art.

The dosage will also depend on the route of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively high doses must be administered. Oral administration is the preferred method of administration of the compounds of this invention.

Preferably the composition is in unit dosage form. For oral administration, tablets or capsules can be administered, for example. For nasal administration, metered dose aerosols can be administered, for transdermal administration, topical formulations or patches can be administered, for transmucosal delivery, buccal patches can be administered. . In each case, administration is such that the patient can administer a single dose.

Each dosage unit for oral administration is suitably calculated as the free base and of the formula (
I) or a pharmaceutically acceptable salt thereof, 0.01 to 500 mg / k
g, preferably 0.1 to 50 mg / kg. The daily dose for parenteral, nasal, oral inhalation, transmucosal or transdermal routes is suitably of formula (I
) The compound represented by the formula () is contained in an amount of 0.01 mg to 100 mg / kg. Topical formulations suitably contain 0.01-5.0% of a compound of formula (I). The active ingredient may be administered 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as will be readily apparent to those skilled in the art.

As used herein, “treatment” of a disease includes prevention, delay, prevention of the disease,
Treatments and cures include, but are not limited to. As used herein, a “disease” treatable with the compound of the present invention includes keratitis, encephalitis, herpes labialis, neonatal disease, genital herpes, varicella, herpes zoster, pneumonia, colitis, retinitis, Giant cell inclusion body disease, rose rash, febrile seizure, bone marrow transplant suppression (bone mar
row graft suppression), interstitial pneumonia, multiple sclerosis, mononucleosis, Burkitt lymphoma, nasopharyngeal cancer, Hodgkin's disease, Kaposi's sarcoma, and multiple myeloma is not.

The compositions of the compounds of formula (I) and their pharmaceutically acceptable salts, which are active when administered orally, can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier such as ethanol, peanut oil, olive oil, glycerine or water containing flavoring or coloring agents. When the composition is in the form of a tablet, the pharmaceutical carriers conventionally used in preparing solid formulations can be used. Examples of such carriers include magnesium stearate, clay,
There are talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, conventional encapsulation, such as with the above carrier in a hard gelatin capsule shell, is suitable. When the composition is in the form of a soft gelatin shell capsule, pharmaceutical carriers conventionally used for preparing dispersions or suspensions, such as aqueous gums, celluloses, silicates or oils, are considered, Entrapped in a soft gelatin capsule shell.

A typical parenteral composition may be a sterile aqueous or non-aqueous liquid containing a compound or salt of a parenterally acceptable oil such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. It consists of a solution or suspension in an aqueous carrier.

A typical inhalable composition may be administered as a dry powder or in the form of an aerosol using conventional propellants such as dichlorodifluoromethane or trichlorofluoromethane, solutions, suspensions. It is a turbid or emulsion dosage form.

[0195] A typical suppository formulation will contain a binder and / or lubricant such as polymeric glycol, gelatin, cocoa butter or other low melting vegetable waxes or fats, or synthetic analogues thereof. It comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered by the method.

A typical transdermal formulation comprises a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste, or is in the form of a pharmaceutical plaster, patch or film. .

Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.

No unacceptable toxicological effects are expected when the compounds of the present invention are administered in accordance with the present invention.

The HCV NS5B inhibitory activity of the compounds of formula (I) is well known to the person skilled in the art, eg Behrens et al., EMBO J. 15: 12-22 (1996) and Lohmann.
It is determined using standard methods described in et al., Virology 249: 108-118 (1998).

All publications, including but not limited to patents and patent applications, cited herein are specifically and individually cited by reference as if each individual publication was fully disclosed. It is made a part of this specification by citation as if it were explicitly made a part of this specification.

────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4439 A61K 31/4439 A61P 1/16 A61P 1/16 31/00 31/00 31/14 31 / 14 C07D 401/04 C07D 401/04 403/04 403/04 405/04 405/04 405/14 405/14 409/04 409/04 409/14 409/14 417/04 417/04 417/14 417 / 14 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, K Z, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC , LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Thomas Kerr United States 19426 South Collegeville Law, College Building, PA Do 1250 F term (reference) 4C063 AA01 AA03 BB01 CC12 CC25 CC62 CC75 CC76 CC92 DD03 EE01 4C069 AA17 BB08 BB12 BD02 CC03 4C086 AA01 AA02 AA03 AA04 BC07 BC17 BC38 BC82 GA04 GA08 GA10 GA12 MA01 MA04 MA52 NA14 ZA75 ZB32 ZB33

Claims (7)

[Claims] 1. The following formula (I): [Wherein A represents OR ₁ , NR ₁ R ₂ , or R ₁ , wherein R ₁ and R ₂ are hydrogen,
Selected from the group consisting of C _1-6 alkyl, optionally substituted aryl, alkylaryl, arylalkyl; B represents hydrogen, C (O) R ₁ , wherein R ₁ is hydrogen, C _1-6 alkyl, aryl, alkylaryl, arylalkyl selected from the group; C represents hydrogen, C _1-6 alkyl, or optionally substituted aryl; D is OR ₁ , NR ₁ R ₂ or R ₁ , wherein R ₁ and R ₂ are hydrogen,
Selected from the group consisting of C _1-6 alkyl, aryl, alkylaryl, arylalkyl; E represents hydrogen, C _1-6 alkyl, optionally substituted aryl, alkylaryl, arylalkyl; X is C _1-6 alkyl, optionally substituted aryl, alkylaryl,
Represents arylalkyl; n is 1 or 2 or 3]. 2. 2-isobutyl-5-thiophen-2-yl-1- [1- (4
-Trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 5- (3-fluoro-phenyl) -2-isobutyl-1- [1- (4-trifluoromethyl- Phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (3-fluoro-
Phenyl) -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-isobutyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl ] -Pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
-(3-Methoxy-phenyl) -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 5- (2-chloro-5-trifluoromethyl-phenyl) -2-isobutyl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
4-dicarboxylic acid 4-methyl ester; 5- (2-chloro-5-trifluoromethyl-phenyl) -1- [1- (3,4-
Dichloro-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-benzyl-5- (2-chloro-5-trifluoromethyl-phenyl) -1-
[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4
-Dicarboxylic acid 4-methyl ester; 2-benzyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5-
Thiophene-2-yl-pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-benzyl-5- (3-fluoro-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -Pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
3-Fluoro-phenyl) -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-benzyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl ] -Pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 5- (3-bromo-4,5-dimethoxy-phenyl) -2-methyl-1- [1- (
4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid 4-methyl ester; 2-isobutyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl ) -Methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
-Thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid; 2-isobutyl-1- (1-naphthalen-1-yl-methanoyl) -5-thiophen-2-yl-pyrrolidin-2,4-dicarboxylic acid 5-furan-2-yl-2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 2-isobutyl-5-thiazole-2- Yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 2-isobutyl-5-thiophen-3-yl-1- [1- (4-tri Fluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 5-furan-3-yl-2-isobutyl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyro Lysine-2,4-dicarboxylic acid; 2-isobutyl-5-pyridin-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 1- [1- (4-tert-butyl-phenyl) -methanoyl] -2-isobutyl-5
-Thiophen-2-yl-pyrrolidine-2,4-dicarboxylic acid; 1- [1- (4-tert-butyl-phenyl) -methanoyl] -2-isobutyl-5
-Thiazol-2-yl-pyrrolidin-2,4-dicarboxylic acid; 5-benzofuran-2-yl-1- [1- (4-tert-butyl-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2, 4-dicarboxylic acid; 5-benzofuran-2-yl-2-isobutyl-1- [1- (3-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 1- [1- ( 3,4-Dichloro-phenyl) -methanoyl] -2-isobutyl-5
-Thiazol-2-yl-pyrrolidin-2,4-dicarboxylic acid; 1- [1- (4-ethyl-phenyl) -methanoyl] -2-isobutyl-5-thiazol-2-yl-pyrrolidin-2,4- Dicarboxylic acid; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (3-fluoro-
Phenyl) -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
-(3-Methoxy-phenyl) -pyrrolidine-2,4-dicarboxylic acid; 5- (2-chloro-5-trifluoromethyl-phenyl) -1- [1- (3,4-
Dichloro-phenyl) -methanoyl] -2-isobutyl-pyrrolidine-2,4-dicarboxylic acid; 5- (2-chloro-5-trifluoromethyl-phenyl) -2-isobutyl-1
-[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,
4-dicarboxylic acid; 1- [1- (3,4-dichloro-phenyl) -methanoyl] -2-isobutyl-5
-(2,3,5-trichloro-phenyl) -pyrrolidine-2,4-dicarboxylic acid; 5- (3-bromo-4,5-dimethoxy-phenyl) -2-methyl-1- [1- (
4-Trifluoromethyl-phenyl) -methanoyl] -pyrrolidin-2,4-dicarboxylic acid; 2-benzyl-5-thiophen-2-yl-1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -Pyrrolidine-2,4-dicarboxylic acid; 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
3-Fluoro-phenyl) -pyrrolidine-2,4-dicarboxylic acid; 2-benzyl-5- (3-fluoro-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine- 2,4-Dicarboxylic acid; 2-benzyl-5- (3-methoxy-phenyl) -1- [1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4-dicarboxylic acid; 2- Benzyl-5- (2-chloro-5-trifluoromethyl-phenyl) -1-
[1- (4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2,4
-Dicarboxylic acid; 2-benzyl-1- [1- (3,4-dichloro-phenyl) -methanoyl] -5- (
2,3,5-Trichloro-phenyl) -pyrrolidine-2,4-dicarboxylic acid; 4-carbamoyl-2-isobutyl-5-thiazol-2-yl-1- [1- (
4-trifluoromethyl-phenyl) -methanoyl] -pyrrolidine-2-carboxylic acid; 1- [1- (4-tert-butyl-phenyl) -methanoyl] -4-carbamoyl-
2-Isobutyl-5-thiazol-2-yl-pyrrolidin-2-carboxylic acid; 4-carbamoyl-2- (1H-imidazol-4-ylmethyl) -5-thiophen-2-yl-1- [1- (4 -Trifluoromethyl-phenyl) -methanoyl]
A compound according to claim 1 selected from the group consisting of -pyrrolidine-2-carboxylic acid. 3. A method of treating or preventing an infection, the method comprising administering to a subject in need of such treatment or prevention an effective amount of a compound of claim 1. 4. The method of claim 3, which comprises inhibiting HCV. 5. The method of claim 3, wherein the compound is administered in an oral dosage form. 6. The method for synthesizing a compound according to claim 1, comprising the step of using a solid phase binding reagent. 7. The method according to claim 6, wherein the reagent is an amino acid.